Prevention of Future Deaths reports · 2018
Regulation 28 report to prevent future deaths, reference 2018-0279, written 8 Oct 2018. A coroner writes one of these when an inquest reveals a risk that could cause further deaths unless something changes.
| Date of report | 8 Oct 2018 |
|---|---|
| Reference | 2018-0279 |
| Deceased | Natasha Ednan-Laperouse |
| Coroner | Sean Cummings |
| Coroner area | West London |
| Category | Other related deaths |
| Source | judiciary.uk record · original PDF |
| Responses published | 2 |
Text extracted from the PDF text layer. Reproduced verbatim, including the scan's own layout.
REGULATION 28: REPORT TO PREVENT FUTURE DEATHS NOTE: This form is to be used after an inquest. REGULATION 28 REPORT TO PREVENT FUTURE DEATHS THIS REPORT IS BEING SENT TO: 1. 2. 3. 4. Clive Schlee, Chief Executive of Pret-a-Manger The MHRA the Chief Executive of Pfizer makers of the Epipen Mr Michael Gove Secretary of State Department for the Environment, Food and Rural Affairs 1 CORONER I am Dr Séan Cummings Assistant Coroner for the Coroner Area of London (Western Area) 2 CORONER’S LEGAL POWERS I make this report under paragraph 7, Schedule 5, of the Coroners and Justice Act 2009 and regulations 28 and 29 of the Coroners (Investigations) Regulations 2013. 3 INVESTIGATION and INQUEST On 03/08/2016 I commenced an investigation into the death of Natasha Charlotte Rose Ednan-Laperouse, 15 years old. The investigation concluded at the end of the inquest on 28/09/2018.The conclusion of the inquest was (2) Anaphylaxis (4) Natasha Ednan- Laperouse died of anaphylaxis in Nice on the 17th July 2016 after eating a baguette, purchased from Pret-a-Manger at LHR T5. The baguette was manufactured to Pret specifications and contained sesame to which she was allergic. There was no specific allergen information on the baguette packaging or on the langar barker and Natasha was reassured by that. 4 CIRCUMSTANCES OF THE DEATH Natasha travelled with her father and friend for a short holiday in Nice on the 17th July 2016. She was allergic to sesame. She bought a baguette after checking the ingredients. She had eaten at Pret previously and was reassured by what she took to be their high standards. She ate the baguette. The baguette contained unlabelled sesame at a ratio of 2.41% expressly commissioned by Pret. She developed an anaphylactic reaction on the plane to Nice and despite best efforts succumbed to that, dying in hospital in Nice shortly after landing. 5 CORONER’S CONCERNS During the course of the inquest the evidence revealed matters giving rise to concern. In my opinion there is a risk that future deaths could occur unless action is taken. In the circumstances it is my statutory duty to report to you. The MATTERS OF CONCERN are as follows. – (1) That allergens were not labelled adequately or clearly on Pret-a-Manger packaging when prepared in their kitchens “pre-packed for direct sale” 1 utilising regulation 5 of the Food Information Regulations. Regulation 5 allows for food outlets to avoid full food labelling requirements whether they prepare a small number of items in local shops or in the case of Pret, over 200 million items for sale by preparing these items in “local kitchens”. These items prepared in “local kitchens” are in fact “assembled” in large parts from items made in factory style outlets to Pret specifications. I was left with the impression that the “local kitchens” were in fact a device to evade the spirit of the regulation. (2) In the case of Pret-a-manger there was no coherent or co-ordinated system for monitoring customer allergic reactions despite sales of more than 200 million items. In some cases concerns were notified to Customer Services and in some they were noted to the safety department. The two did not know what the other was responding to. It was clear that there was no overarching monitoring system in place. In response to questioning on this I was told that the manager responsible for safety now received all notifications and would monitor them. In my view this remains highly inadequate. In my view sales of 200 million items some with expressly commissioned but hidden allergens require a robust safety auditing system. The previous system was unsafe and the system proposed equally so in my view. (3) In the Emergency treatment of anaphylactic reactions Guidelines for healthcare providers the preferred needle length is 25 mm for adrenaline injectors to access muscle in most people. I heard during expert evidence that Epipen needle length was 16mm - suitable according to the UK Resuscitation Council for “pre-term or very small infants”. The use of needles which access only subcutaneous tissue and not muscle is in my view inherently unsafe. An alternative autoinjector, Emerade has a 24 mm needle. (4) The dose of adrenaline in Epipen is 300mcg. The UK Resuscitation Council recommends a standard emergency dose of 500mcg. Emerade contains a dose including 500mcg. The combination of what my expert told me was an inadequate dose of adrenaline for anaphylaxis and an inadequate length needle raises serious safety concerns. 6 ACTION SHOULD BE TAKEN In my opinion action should be taken to prevent future deaths and I believe you (1) Clive Schlee Chief Executive of Pret-a-Manger; The MHRA; the Chief Executive of Pfizer and Michael Gove, Secretary of State have the power to take such action. 7 YOUR RESPONSE You are under a duty to respond to this report within 56 days of the date of this report, namely by 3rd December 2018. I, the Coroner, may extend the period. Your response must contain details of action taken or proposed to be taken, setting out the timetable for action. Otherwise you must explain why no action is proposed. 8 COPIES and PUBLICATION I have sent a copy of my report to the Chief Coroner and to the following Interested Persons (1) The Laperouse Family, (2) Clive Schlee Chief Executive Pret-A-Manger; (3) The MHRA (4) The Secretary of State Michael Gove and to the LOCAL SAFEGUARDING BOARD. I am also under a duty to send the Chief Coroner a copy of your response. The Chief Coroner may publish either or both in a complete or redacted or summary 2 form. He may send a copy of this report to any person who he believes may find it useful or of interest. You may make representations to me, the coroner, at the time of your response, about the release or the publication of your response by the Chief Coroner. 8th October 2018 9 3 Dr Séan Cummings Assistant Coroner LondonWest
2 responses published against this report on judiciary.uk. A response is a body's written reply to the coroner's concerns; publication is at the discretion of the Chief Coroner's office, so an absent response does not mean nobody replied.
POR The Rt Hon Michael Gove MP Rie From the Secretary of State for Environment, Food Department and Rural Affairs for Environment Seacole Building T 03459 335577 : 2 Marsham Street defra.helpline@defra.gsi.gov.uk Food & Rural Affairs London SW1P 4DF www.gov.uk/defra 27” November 2018 Thank you for your letter concerning the inquest into the death of Natasha Ednan- Laperouse who died tragically of anaphylaxis after eating a baguette purchased from Pret- a-Manger at London Heathrow Airport. First, | would like to express my most sincere condolences to the Ednan-Laperouse family. My heart goes out to her family and friends. | very much appreciate your efforts to ensure that this important investigation and inquest was conducted with rigour and independence. | have carefully considered your report and offer the following in response to the detailed issues you have raised which are pertinent to my department. The first matter of concern (1) you raise relates to inadequate allergen labelling on products which are, according to the relevant legislation, “pre-packed for direct sale”. Current food information regulations, which date from 2014, make a distinction between pre-packed food found, for example, in a supermarket, and food pre-packed for direct sale, for example in a food-to-go outlet, where food is prepared and packed on the premises for sale. In the latter, there is currently no requirement to label an individual product with allergen information, provided that information is readily discernible, including through indications to ask a member of staff. Taking into account matter of concern (1) raised in your Regulation 28 report, an urgent review of allergen information provision for food which is pre-packed for direct sale is under way with a view to strengthening the framework. The provision of allergen information to the public is a hugely important issue, and it is essential that all UK consumers have complete trust in the food they are eating. The Department for Environment, Food and Rural Affairs (Defra) is working on this review closely with the Food Standards Agency (FSA) and the Department for Health and Social Care (DHSC). We are also working closely with the Devolved Administrations to ensure that the review is UK wide. To date, officials from Defra and the FSA have held joint meetings with a number of key stakeholders, including key industry representatives, a range of businesses and allergy patient groups, and this dialogue will continue over the following months. Through these discussions, stakeholders have highlighted the potential of both regulatory and non- regulatory approaches to strengthen the current framework on allergens, and we are developing a number of policy options based on this information with a view to formal consultation. Our central concern is about improving consumer safety, and therefore, alongside the review, we are encouraging businesses to implement a best practice approach to allergen information provision. The FSA have also been working in collaboration with patient groups to run awareness campaigns such as #EasytoASK which works to promote best practice behaviour by consumers with allergies. We must act quickly to ensure that we have the best possible protection for consumers in place as soon as possible. Consequently, we aim to launch our consultation on allergen information provision policy options early in the new year and any legislation that is needed will follow as soon as possible. While the second matter of concern you raise relates to notification systems for allergen- related incidents within businesses, | wanted to take this opportunity to set out some related activity undertaken by Government. The FSA have been working with local authorities in Lancashire on a pilot scheme to improve the notification of incidents between businesses, local authorities and the NHS. Such a system would allow local authorities to work with specific Food Business Operators to help them better understand their obligations and requirements and, understand the significance of the potential health and financial consequences of non-compliance. | am grateful for your report, welcome publication of this response, and can assure you of my commitment to take the necessary steps to ensure that the public have the allergen information that they need to inform their food choices. Thank you again for your report. With every good wish, M UM bon Michael Gove
Dr Sean Cummings Assistant Coroner London West West London Coroner’s Office Coroner’s Court 25 Bagleys Lane Fulham, London SW6 2QA 29 November 2018 Dear Dr Cummings, Medicines and Healthcare products Regulatory Agency 10 South Colonnade Canary Wharf London E14 4PU United Kingdom +44 (0) 20 3080 6000 gov.uk/mhra Regulation 28 Report concerning Natasha Ednan-Laperouse Thank you for your letter of 9th October 2018 in which you asked the MHRA to provide a response to the Regulation 28 Report to Prevent Future Deaths following the inquest into the tragic death of Natasha Ednan-Laperouse. Your report listed two matters of concern that fall under the remit of the MHRA and medicines regulation. Your concerns relate to the effectiveness of Epipens, a brand of adrenaline auto-injector carried by at- risk patients for self-administration to treat anaphylaxis before the arrival of the emergency services. Your concerns specifically relate to the adequacy of needle length and adrenaline dose when compared with published guidelines from the UK Resuscitation Council. Concern (3) – needle length: It is widely accepted by clinical experts that adrenaline should be delivered into muscle tissue to maximise the chance of recovery from anaphylaxis, a recommendation endorsed by the UK Resuscitation Council. It is clear from the Epipen Summary of Product Characteristics (information for the prescriber), relevant sections from which are displayed in Annex 1, that intramuscular delivery is the intended route of administration: “EpiPen® auto injector is for adult intramuscular administration.” You question whether the exposed needle length of Epipen (16 mm) is adequate to reach muscle in most patients. The adequacy of adrenaline auto-injector needle length was addressed by the MHRA as one aspect of a review in 2014. The available evidence was found to be lacking in some key aspects and the MHRA therefore took this forward as part of a wider European safety review that reported on 25 June 2015. As one of the legally binding conditions following the European safety review, manufacturers were required to disclose the exposed needle length of their adrenaline auto-injector devices in the product information to inform the healthcare professional and patient so they can take this in to account in deciding which device is appropriate for an individual patient. The exposed needle length of the three pens that are marketed in the UK are specified in the Summary of Product Characteristics (SmPC) and patient leaflet, and are as follows: Epipen 0.3 mg (16 mm), Jext 300 mcg (15 mm), Emerade (23 mm). For clarification, the preferred needle length of 25 mm that you refer to in your report is recommended by the UK Resuscitation Council in the context of anaphylaxis treatment by healthcare professionals, when adrenaline is recommended to be administered by manual intramuscular injection with a syringe 1 and needle, a method not suitable for self-administration. The UK Resuscitation Council had cause to clarify this, in response to recent media reports that had misinterpreted its guidance: https://www.resus.org.uk/media/statements/statement-on-anaphylactic-guidelines/ Needles that are too long are not without risk: a needle that is too long can strike bone which has been reported to result in needle fracture and, rarely, in injection of adrenaline into the bone cavity which can mimic intravenous delivery. Where a needle is deployed with force, these risks are likely to be higher. Adrenaline auto-injectors are designed to forcibly deploy a needle, through clothing if necessary to save time, in the immediate period following the onset of anaphylactic symptoms. Auto-injectors are intended to deliver adrenaline into muscle tissue by a combination of both direct needle penetration and propulsive force of the device. The manufacturer of Epipen asserts that the propulsive force of the device will allow adrenaline to reach muscle even if the device needle is deployed subcutaneously. The European safety review endorsed that delivery of adrenaline into muscle tissue is the preferred way to treat anaphylaxis in the early, time critical, period before the arrival of the emergency services. However, the review considered that the evidence was not sufficiently robust to support the assertion of intramuscular penetration of adrenaline following auto-injector deployment. The review concluded that adrenaline auto-injectors are in the main effective and undoubtedly save lives but studies in human volunteers were needed to investigate whether the speed and amount of adrenaline taken up into the bloodstream following auto-injector deployment was consistent with intramuscular penetration of adrenaline. The requirement for clinical studies – in human volunteers - was imposed by the European Commission for all brands of adrenaline auto-injectors marketed throughout Europe. In the UK, this applies to the three brands of adrenaline auto-injectors that are marketed: Epipen, Jext and Emerade. Your principal concern is with the Epipen brand given that Natasha failed to respond to two Epipen auto- injectors. The administration of a second adrenaline auto-injector 5 to 15 minutes after the first, if the patient has not responded adequately, is recommended in the instructions for use in the product information for prescriber and patient. The review of clinical study results for Epipen undertaken by the MHRA and other competent authorities throughout Europe commenced on 15th September 2018. The MHRA raised questions which the company is currently addressing and will result in further information being submitted for evaluation. Regulatory action will be taken as necessary on completion of the review. For illustrative purposes, clinical study results for the Jext 300 mcg device, submitted prior to the Epipen data, are summarised below. You should be aware that results cannot be extrapolated between different brands of adrenaline auto-injector given that the rate and extent of adrenaline absorption will not only depend on adrenaline dose and needle length but also on the propulsive force of the device as well as the formulation of the adrenaline solution. Individual clinical study results for each device therefore need to be evaluated. The Jext data nonetheless serve to illustrate the types of measures that can be implemented even in the short term, such as factual disclosure of study data in the SmPC, to inform the prescriber and patient. The study data for the Jext 300 mcg device were submitted to the UK and other European countries where the product is marketed on 21 December 2017 and the evaluation was concluded on 17 October 2018. This informed subsequent updating of the Summary of Product Characteristics (SmPC) and patient leaflet, Annex 2. The study found that, in subjects with a skin to muscle depth greater than 20 mm, adrenaline absorption into the systemic circulation was slower following Jext compared with manual intramuscular injection (using syringe and needle); moreover, in the same subjects, the overall amount of adrenaline reaching the circulation in the first 8, 16 and 30 minutes – the early, time critical period - was lower following Jext injection compared with manual intramuscular injection (these results are 2 available to the prescriber in section 5.2 of the SmPC – see Annex 2). As a consequence additional warnings have now been implemented in section 4.4 of the SmPC that patients with a thicker subcutaneous fat layer may be at increased risk of an inadequate response and may therefore be more likely to need a second injection. Disclosure of clinical study data to the prescriber within the SmPC, with appropriate specialist clinical guidance, will enable translation of the evidence into clinical practice to inform a decision on suitability of the Jext 300 mcg auto-injector for a particular patient, or whether an alternative device may be advisable. A full report on the studies is expected to be published by end December 2018 by Sweden, the Competent Authority coordinating the evaluation. Results for Emerade, the third brand of adrenaline auto-injector currently marketed in the UK, are expected to be submitted for evaluation in February 2019. This delayed submission date was agreed by the European Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) due to local ethical committee requirements for screening of patients. It is foreseen that the evaluation of results for all adrenaline auto-injectors marketed in the UK (Epipen, Jext and Emerade) will be completed during 2019. The availability of data on exposed needle length for all devices, together with the results of clinical studies, will allow an informed decision to be taken on prescribing and advice given to patients. When all study data are available, an over-arching evaluation is intended, to inform whether further measures may be required, that may include a recommendation for longer needle lengths. Additional outcomes from the European safety review recommended for implementation in the meantime were: Recommendations for improved training and educational materials for patients, carers and - healthcare professionals in the use of adrenaline auto-injectors. - Improvements to the product information for prescriber and patient, including strengthening of the recommendation that patients should carry two auto-injectors to enable a second injection if there has been an insufficient response within the first 15 minutes; and reinforcement of the need for family members, carers and teachers to be properly trained in use of the patient’s auto-injector. A requirement for disclosure of exposed needle length for the respective devices in the product - information to inform the healthcare professional and patient. - These outcomes have been implemented for all adrenaline auto-injector products sold in the UK. The MHRA has in the meantime published updated advice on the use of adrenaline auto-injectors to patients and their carers: https://assets.publishing.service.gov.uk/media/5b644e25ed915d377695c83d/AAI-PDF-v4.pdf Concern (4) – adequacy of adrenaline dose in Epipen: You question whether a 300 mcg dose of adrenaline – delivered by the adult presentation of Epipen - is adequate to treat anaphylaxis, given the UK Resuscitation Council recommendation that 500 mcg is the dose recommended to treat anaphylaxis. A discrete, efficacious dose of adrenaline for the emergency treatment of anaphylaxis is not defined. The Resuscitation Council guidance for a 500 mcg dose refers to the dose administered by a healthcare professional (by manual intramuscular injection with a syringe and needle) and is not their recommended dose for adrenaline auto-injector self-administration. In a healthcare setting, a second dose of 500 mcg adrenaline is recommended to be administered after 5 minutes if the patient is not responding. An experienced specialist could also treat anaphylaxis with repeated bolus doses of 50mcg of intravenous adrenaline or may initiate intravenous infusion of adrenaline according to the response. In the healthcare 3 setting described above, cardiovascular monitoring can be initiated due to the risk of dysrhythmia with high dose adrenaline. The above treatment regimens are not appropriate in the circumstance where a patient needs to self- administer their adrenaline-autoinjector prior to the arrival of emergency services. In the same clarification statement referred to above https://www.resus.org.uk/media/statements/statement-on-anaphylactic-guidelines/ the Resuscitation Council clarifies the basis of their recommendation for a 500 mcg dose: “With regards to dose recommendations, we would like to stress that 500 mcg is the dose healthcare professionals should give to patients over 12 years of age and is not, as has been incorrectly quoted, an RC (UK) recommendation for the provision of adrenaline through auto-injectors.” Although a single Epipen dose in the adult presentation delivers 300 mcg of adrenaline, patients are advised to carry two adrenaline auto-injectors at all times and that a second injection should be given 5 to 15 minutes after the first injection if there has been an inadequate response. The authorised instructions for use therefore allow an adrenaline dose of 600 mcg to be self-administered. An early lack of response to a first injection cannot, from the available evidence, be predicted with any degree of reliability for a given patient; this underpins the MHRA’s continuing recommendation that patients should carry two auto-injectors, which was reinforced in the European safety review. An early lack of response should also be distinguished from the phenomenon of biphasic anaphylaxis that can occur several hours later after an apparently good initial response to emergency treatment. A risk of biphasic anaphylaxis is one reason patients must summon an ambulance even if there has been an apparently good response to auto-injector administration. Conclusion The MHRA has, as outlined, taken action in undertaking a review of adrenaline auto-injectors, and has progressed this within Europe, following which a number of outcomes including improved training, additional risk minimisation measures and factual disclosures within the product information have been implemented. The review concluded that adrenaline auto-injectors are in the main effective and undoubtedly save lives but studies in human volunteers were required to determine whether the speed and amount of adrenaline taken up into the bloodstream following auto-injector deployment is consistent with intramuscular penetration of adrenaline. The MHRA is presently undertaking a rigorous evaluation of the clinical study data for each brand of adrenaline auto-injector as and when it is submitted, and will ensure any necessary measures are taken in order to increase the effectiveness of adrenaline auto- injectors in the emergency treatment of anaphylaxis. If necessary, the prescribing information for each auto-injector will be updated as an immediate measure as soon as conclusions on the data have been reached. When data on all products are available – anticipated during 2019 – an over-arching evaluation will be conducted by the MHRA that will inform the need for any further measures. I will write to you following the completion of the evaluation of the clinical data for Epipen to inform you of any recommendations or regulatory actions that may be deemed necessary to protect public health. Yours sincerely Dr Ian Hudson Chief Executive 4
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